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EP1714691B1 - Méthode pour ôter le monoxyde de carbone d'un transporteur d'oxygène telle l'hémoglobine et appareil associé - Google Patents

Méthode pour ôter le monoxyde de carbone d'un transporteur d'oxygène telle l'hémoglobine et appareil associé Download PDF

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Publication number
EP1714691B1
EP1714691B1 EP06007915A EP06007915A EP1714691B1 EP 1714691 B1 EP1714691 B1 EP 1714691B1 EP 06007915 A EP06007915 A EP 06007915A EP 06007915 A EP06007915 A EP 06007915A EP 1714691 B1 EP1714691 B1 EP 1714691B1
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European Patent Office
Prior art keywords
oxygen
oxygen carrier
carbon monoxide
hollow fiber
dissolved solution
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German (de)
English (en)
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EP1714691A1 (fr
Inventor
Ippei c/o NIPRO CORPORATION Fukutomi
Toshiya c/o NIPRO CORPORATION Kai
Naohisa c/o NIPRO CORPORATION Katayama
Ken c/o NIPRO CORPORATION Nitsuka
Yoshinori c/o NIPRO CORPORATION Kida
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Nipro Corp
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Nipro Corp
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/14—Ultrafiltration; Microfiltration
    • B01D61/20—Accessories; Auxiliary operations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A61K38/42—Haemoglobins; Myoglobins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D19/00—Degasification of liquids
    • B01D19/0005—Degasification of liquids with one or more auxiliary substances
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D19/00—Degasification of liquids
    • B01D19/0031—Degasification of liquids by filtration
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/36—Pervaporation; Membrane distillation; Liquid permeation
    • B01D61/365—Osmotic distillation or osmotic evaporation

Definitions

  • the present invention relates to a method of treating an oxygen carrier.
  • the present invention more specifically relates to a method of treating an aqueous solution containing a carbon monoxide bonded oxygen carrier, that is, a method of performing a carbon monoxide removal treatment on an oxygen carrier to remove carbon monoxide for the stabilization of the oxygen carrier.
  • Carbon monoxylation of an oxygen carrier is used for preventing inactivation of an oxygen transport function of hemoglobin over a long period of time.
  • the present invention also relates to an apparatus for the treatment.
  • oxygen carriers there are natural oxygen carriers and artificial oxygen carriers.
  • the natural oxygen carriers include hemoglobin originated from, for example, humans, bovines, or other living organisms; concentrated red blood cells or myoglobin originated from, for example, humans, bovines, or other living organisms; and hemocyanin originated from, for example, fish or other living organisms.
  • artificial oxygen carriers examples include highly-functional oxygen carriers that utilize natural oxygen carriers, such as modified hemoglobin and hemoglobin-encapsulated liposomes; completely-synthesized oxygen carriers, such as compounds in which porphyrin metallic complexes inclusive of porphyrin derivatives are incorporated in albumin, albumin dimers, and albumin polymers; and perfluorocarbons; and recombinant oxygen carriers, such as recombinant hemoglobin, recombinant modified hemoglobin, modified recombinant hemoglobin, and recombinant hemoglobin-encapsulated liposomes, which can be obtained by gene recombination technologies. These oxygen carriers can replace red blood cells of humans and other animals.
  • natural oxygen carriers such as modified hemoglobin and hemoglobin-encapsulated liposomes
  • completely-synthesized oxygen carriers such as compounds in which porphyrin metallic complexes inclusive of porphyrin derivatives are incorporated in albumin, albumin dimers, and albumin polymers
  • oxygen carriers are used for oxygen supply to an ischemic site or tumor tissue, for blood transfusion to a patient with massive bleeding, for an organ-preserving perfusion fluid, for an extracorporeal circulation fluid, for a cell culture medium, and so on (see, e.g., JP2004-307404A , A paragraph [0008], paragraph [0009], or Examples in paragraph [0039] regarding a method of preparing a hemoglobin-encapsulated liposome or JP 2004-277329 , A paragraph [0002] or paragraph [0003] or Komatsu et al., Artificial blood, vol.6, p.110-114, 1998 , lines 16 to 19, left hand column, p.111).
  • porphyrin metal complex is a 2-[8-(2-methyl-1-imidazolyl)octanoyloxymethyl]-5,10,15,20-tetrakis[ ⁇ , ⁇ , ⁇ , ⁇ -o-(1-m ethylcyclohexanoylamino)phenyl]porphinato complex ( Bioconjugate Chem., vo1.13, p.397-402, 2002 ).
  • the hemoglobin-encapsulated liposome includes a hemoglobin encapsulated in an inner layer of a liposome formed of a lipid bilayer, and various preparation methods and investigations thereof have been studied ( JP2004-307404A , A paragraph [0008], paragraph [0009], or Examples in paragraph [0039] regarding a method of preparing a hemoglobin-encapsulated liposome).
  • the artificial oxygen carriers having divalent heme iron in an artificial oxygen carrier molecule have an oxygen transport function.
  • An artificial oxygen carrier having the heme iron oxidized into trivalent heme iron, that is, an artificial oxygen carrier which lose ability of oxygen coordination has no oxygen transport function.
  • formation of the met- artificial oxygen carrier must be prevented.
  • a known method of preventing the formation of the "artificial oxygen carrier which lose ability of oxygen coordination involves formation of a complex of heme iron and carbon monoxide in the artificial oxygen carrier molecule, that is, stabilization of the artificial oxygen carrier through carbon monoxylation ( Methods in ENZYMOLOGY, vol.76, HEMOGLOBINS, ACADEMIC PRESS, p.9, 1981 ).
  • the artificial oxygen carrier which is stabilized through formation of a complex of heme iron bonded carbon monoxide never after sometimes referred to as a carbon monoxide bonded artificial oxygen carrier has no oxygen transport function.
  • carbon monoxide which forms the complex with heme iron in the artificial oxygen carrier must be removed, in other words, de-carbon monoxylation must be carried out, before the carbon monoxide bonded artificial oxygen carrier is used as a red blood cell alternative, for recovering the oxygen transport function of the artificial oxygen carrier.
  • a known method of recovering the oxygen transport function by removing carbon monoxide from the carbon monoxide bonded artificial oxygen carrier involves introducing an artificial oxygen carrier solution into a round bottom flask in a volume of about 1 /100 of that of the flask; exposing the solution in an ice bath to light of 200 W; and blowing oxygen into the solution for 10 minutes while the flask is rotated ( Methods in ENZYMOLOGY, vol.76, HEMOGLOBINS, ACADEMIC PRESS, p.164, 1981 ).
  • a known modified method thereof involves using a hollow fiber formed of a porous hollow fiber membrane; applying an oxygen gas pressure through the hollow fiber membrane from the outer side of the membrane; allowing passage of an aqueous solution containing a carbon monoxide bonded artificial oxygen carrier from an inner side of the hollow fiber membrane; and removing carbon monoxide from the artificial oxygen carrier in the aqueous solution under light ( JP 06-329550 A , A paragraph [0008] and the like, for example 4).
  • an object of the present invention is to provide a method of continuously removing carbon monoxide from a carbon monoxide bonded oxygen carrier with a high productivity.
  • an object of the present invention is to provide a method that does generally not cause denaturation of proteins and the like.
  • an oxygen gas has a low heat exchange rate, and heat accumulation is easily caused by light. As a result, degradation of a hollow fiber membrane and denaturation of the artificial oxygen carrier are liable to occur.
  • the present invention has been made in view of the above-mentioned problems.
  • the inventors of the present invention have conducted extensive studies, and have found that an oxygen carrier subjected to carbon monoxide removal can be obtained by providing a carbon monoxide bonded oxygen carrier solution across a separation membrane from a solution in which oxygen is dissolved (hereinafter referred to as an oxygen-dissolved solution); and exposing the separation membrane as a reaction plane to light, i.e., a plane where light raises electrons from one energy level to another and carbon monoxide comes free from the oxygen carrier and the oxygen carrier without a ligand coordinates with oxygen.
  • an oxygen-dissolved solution a carbon monoxide bonded oxygen carrier solution across a separation membrane from a solution in which oxygen is dissolved
  • the present invention relates to the following.
  • the method of removing carbon monoxide from an oxygen carrier according to claim 1 can prevent denaturation of proteins and the like by concentration of the oxygen carrier. At the same time, the method can prevent degradation of membrane performance related to drying of the separation membrane.
  • a large heat exchange rate between solutions can suppress heat accumulation by light, to thereby prevent degradation of the separation membrane and denaturation of the oxygen carrier by heat.
  • An apparatus for performing continuous treatment of removing carbon monoxide from an oxygen carrier can be designed by using the separation membrane.
  • productivity can be enhanced compared with that of a batch method such as conventional treatment in a round bottom flask.
  • the oxygen carrier passes only through a light exposing portion when the separation membrane is placed only in a surface or so portion of a membrane module to be exposed as the reaction plane to light.
  • removal of carbon monoxide can be more effectively carried out.
  • the present invention relates to a method of continuously removing carbon monoxide from an oxygen carrier according to claim 1, and to an apparatus for continuously removing carbon monoxide according to claim 3.
  • the apparatus includes an oxygen carrier circulation vessel 1 connected to the hollow fiber membrane module (3) via the oxygen carrier supply line (5'); an oxygen-dissolved solution circulation vessel 2; a hollow fiber membrane module 3 which includes an ultrafiltration membrane or a filtration filter; a light source 4 which includes an incandescent light, a halogen lamp, a light-emitting diode, a sodium vapor lamp, or a metal halide lamp; an oxygen carrier circulation pump 5; an oxygen carrier supply line 5'; an oxygen carrier recovery line 5"; an oxygen-dissolved solution circulation pump 6; an oxygen-dissolved solution supply line 6'; an oxygen-dissolved solution recovery line 6"; an oxygen-dissolved solution supply pump 7; an oxygen supply line 8; a flow control valve 9; and a stirrer and a blade thereof 10.
  • an oxygen carrier supplied from the oxygen carrier circulation vessel 1 with pump 5 is subjected to carbon monoxide removal by an oxygen-dissolved solution supplied from the oxygen-dissolved solution circulation vessel 2 and light from the light source 4 in the hollow fiber membrane module 3, and then is returned to the oxygen carrier circulation vessel 1.
  • oxygen-dissolved solution supplied from the oxygen-dissolved solution circulation vessel 2 connected to the hollow fiber membrane module 3 via the oxygen-dissolved solution supply line 6' with pump 6 supplies oxygen into the hollow fiber membrane module 3 and receives carbon monoxide from the oxygen carrier, and then is returned to the oxygen-dissolved solution circulation vessel 2.
  • Carbon monoxide in the returned solution is discharged from the returned solution through a gas discharge line 8', as the returned solution is replenished with oxygen gas from the oxygen supply line 8.
  • an apparatus such as that shown in Fig. 4 , in which an oxygen carrier is recovered continuously without circulation of a carbon monoxide bonded oxygen carrier solution, may be used for performing the method of the present invention. That is, the apparatus includes: an oxygen carrier storage vessel 17; an oxygen-dissolved solution circulation vessel 18; a hollow fiber membrane module A 19; a hollow fiber membrane module B 20; a hollow fiber membrane module C 21; a light source A 22; a light source B 23; a light source C 24; an oxygen carrier circulation pump 25; an oxygen-dissolved solution circulation pump 26; an oxygen supply line 27; and a vessel 28 for recovering an oxygen carrier subjected to carbon monoxide removal.
  • the oxygen carrier subjected to carbon monoxide removal can be recovered continuously, to thereby drastically enhance its production efficiency.
  • Fig. 1 the apparatus of the present invention is shown in Fig. 1 .
  • the oxygen carrier to be used in the present invention with divalent heme iron in an oxygen carrier molecule has an oxygen transport function.
  • the oxygen carrier may be one material or a combination of two or more kinds of materials selected from for example the group consisting of a hemoglobin-encapsulated liposome; a porphyrin metal complex-including albumin, a porphyrin metal complex/ PEGylated albumin composite, a hemoglobin solution, a molecular bridge-hemoglobin, a hemoglobin polymer, and a PEG-hemoglobin polymer.
  • the oxygen carrier to be used may have a particle size of about 5 nm to 8 ⁇ m, and preferably about 5 nm to 450 nm to be used as a red blood cell alternative.
  • a separation membrane to be used may be in a planar form or a hollow fiber form.
  • a material for the separation membrane is generally a material used for an ultrafiltration membrane or a filtration filter, and is preferably polysulfone, cellulose triacetate, cellulose diacetate, polycarbonate, polyethersulfone, or a polyphospholipid polymer.
  • the size of pores present on the surface of the membrane may be selected in accordance with the particle size of the oxygen carrier, and the pore size must be smaller than the particle size of the oxygen carrier.
  • the separation membrane to be used has a pore size of generally 5,000 nm to 0.001 nm, and preferably 10 nm to 0.10 nm.
  • the form of the separation membrane is not particularly limited. A planar separation membrane is advantageous in view of light exposure, but a hollow fiber separation membrane may also be used.
  • the separation membrane module as used in the present invention refers to a unit for protecting a separation membrane and retaining the separative power thereof, which is constructed of, for example, a separation membrane for removing carbon monoxide, a housing for fixing and protecting the separation membrane, a connector for securing a flow path, and a gasket for isolation of a flow path and prevention of liquid leakage.
  • a hollow fiber is used as a separation membrane
  • a planar membrane it is referred to as a planar membrane module.
  • the separation membrane module can be provided in planar form or in cylindrical form described later when the hollow fiber membrane module is configured as the setting part of hollow fibers.
  • the case so called housing of the separation membrane module is preferably made of an optically transparent material and at least part of the case, in which the planar membrane or hollow fiber membrane is arranged, is preferably transparent or translucent to transmit light.
  • hollow fiber membrane modules in which hollow fibers are arranged in cylindrical cases are popularly used.
  • hollow fiber membrane modules FB-50UGA (manufactured by NIPRO Corporation) and FB-210UGA (manufactured by NIPRO Corporation) can be used.
  • the arrangement of setting part of a separation membrane only on the light exposing portion leads to an increased opportunity for contact between a carbon monoxide bonded oxygen carrier solution and an oxygen-dissolved solution, and also leads to an increased reaching degree of light, i.e., an increased ratio of oxygen carrier exposed to light, thereby enhancing the efficiency of removing carbon monoxide from the oxygen carrier in the separation membrane module.
  • the setting part of the separation membrane only on the light exposing portion means that the separation membrane is placed such that the separation membrane is exposed to light.
  • a setting part of the separation membrane may be, for example, one in which the separation membrane is placed to diminish a dead space between the separation membrane and the case; or one in which the central part of the separation membrane module, where light hardly reaches, is reduced in size as much as possible.
  • the central portion of a main body case may be filled with a filler to prevent the passage of a sample solution therethrough ( Fig. 9 ) to allow the effective hollow fiber membrane to be stacked in a thickness of 1 cm or less from the lateral side of the case cylinder so as to be placed on the inner surface of the cylindrical case (housing).
  • a filler to prevent the passage of a sample solution therethrough ( Fig. 9 ) to allow the effective hollow fiber membrane to be stacked in a thickness of 1 cm or less from the lateral side of the case cylinder so as to be placed on the inner surface of the cylindrical case (housing).
  • the hollow fiber membrane module may be of an improved version in which a hollow fiber membrane is previously placed on the inner surface of the main body case, an improved version in which the central portion of a normal dialyzer is sealed with a water-impermeable resin, such as urethane, to allow the passage only through the surface of the cylinder, or an improved version in which hollow fibers are placed in a flat case such that the hollow fibers will be in the form of a planar layer form of 1 cm or less in thickness.
  • a water-impermeable resin such as urethane
  • An apparatus employing a separation membrane in a planar form may be an apparatus as shown in Fig. 3 , for example. That is, the apparatus includes an oxygen carrier circulation vessel 1; an oxygen-dissolved solution circulation vessel 2; a planar membrane module 3'; a light source 4; an oxygen carrier circulation pump 5; an oxygen-dissolved solution circulation pump 6, an oxygen-dissolved solution supply pump 7; and an oxygen supply line 8.
  • This apparatus allows uniform light exposure from the light source and is efficient.
  • the providing of a carbon monoxide bonded oxygen carrier solution across a separation membrane from an oxygen-dissolved solution refers to setting in which the carbon monoxide bonded oxygen carrier solution is provided on one side of the separation membrane as a boundary and the oxygen-dissolved solution is provided on another side thereof.
  • the separation membrane has a function of allowing free passage of a solvent, ions, dissolved oxygen in the oxygen-dissolved solution, or carbon monoxide without separation, but preventing passage of the oxygen carrier for its separation.
  • the carbon monoxide bonded oxygen carrier is subjected to carbon monoxide removal by means of oxygen and light supplied through the separation membrane while the carbon monoxide bonded oxygen carrier maintains its concentration.
  • the carbon monoxide bonded oxygen carrier solution may be circulated or the oxygen carrier solution subjected to carbon monoxide removal may be collected without being circulated. Collecting without being circulated enables continuous production of the oxygen carrier solution subjected to carbon monoxide removal.
  • a supply speed of the carbon monoxide bonded oxygen carrier solution may be determined arbitrarily in accordance with the performance of the separation membrane and the like, and a supply amount of the carbon monoxide bonded oxygen carrier solution per unit area of the membrane is preferably 1 L/min/m 2 or less.
  • the oxygen-dissolved solution means a solution containing oxygen dissolved therein by bubbling a pure oxygen gas, air, or the like or by applying pressure to the solution.
  • An oxygen concentration in the solution is not particularly limited, and the solution may be saturated.
  • the oxygen-dissolved solution may be circulated or disposed after use, but is more economically circulated.
  • Oxygen to be supplied also serves to discharge and remove as a gas carbon monoxide in the solution circulated and returned from the separation membrane.
  • the dissolved oxygen concentration is preferably 4 ppm or more.
  • the circulation rate of the oxygen-dissolved solution is affected by properties of the separation membrane.
  • the circulation rate must be set such that a pressure of the oxygen carrier solution to be circulated in a normal direction of the separation membrane achieves equilibrium with the pressure of the oxygen dissolved solution. The equilibrium will be made between the pressure of the oxygen carrier solution and the pressure of the oxygen dissolved solution.
  • the circulation rate is preferably adjusted such that minimum water is lost from the oxygen carrier solution.
  • exposing the setting part of the carbon monoxide bonded oxygen carrier solution and the oxygen-dissolved solution to light means exposing the portion, where the carbon monoxide bonded oxygen carrier encounters oxygen supplied at the periphery of the separation membrane to light, wherein the light source includes an incandescent light, halogen lamp, a light emitting diode, a sodium vapor lamp, or a metal halide lamp.
  • the luminance of a single light source can be used. It can be 500,000 Lm or more, substantially preferably 1 to 500,000 Lm, and more preferably 100 to 200,000 Lm. In addition, two or more light sources each having the luminance mentioned above may be used in combination.
  • the carbon monoxide bonded oxygen carrier solution to be used in the present invention may contain a reducing agent. That is, a sample prepared by treating an oxygen carrier to deoxygenation may include an antioxidant containing a reducing agent as an additive for suppressing an oxidation reaction of divalent heme iron present in the oxygen carrier into trivalent heme iron by oxygen and for preventing degradation of performance of the oxygen carrier.
  • Examples of the natural oxygen carriers subjected to deoxygenation include hemoglobin originated from, for example, humans, bovine, or other living organisms; concentrated red blood cells or myoglobin originated from, for example, humans, bovines, or other living organisms; or hemocyanin originated from, for example, fish or other living organisms.
  • artificial oxygen carriers include highly-functional oxygen carriers that utilize natural oxygen carriers such as modified hemoglobin and hemoglobin-encapsulated liposomes; completely-synthesized oxygen carriers, such as compounds in which porphyrin metallic complexes inclusive of porphyrin derivatives are incorporated in albumin, albumin dimers, and albumin polymers, and perfluorocarbon; various kinds of modified hemoglobin; agents each including a heme complex in albumin, such as a porphyrin metal complex-including albumin, a porphyrin metal complex-including albumin dimer, a porphyrin metal complex-including albumin polymer, a PEG-modified porphyrin metal complex-including albumin, a PEG-modified porphyrin metal complex-including albumin dimer, and a PEG-modified porphyrin metal complex-including albumin polymer; and recombinant carriers such as recombinant hemoglobin, recombinant modified hemoglobin, modified recombinant hemoglobin,
  • hemoglobin-encapsulated liposomes the hemoglobin-encapsulated liposomes, the PEG-modified phenylporphinato iron complex-including albumin or PEG-modified porphyrin metal complex-including albumin, and recombinant hemoglobin-encapsulated liposomes are preferable.
  • one or two or more of reducing agents selected from the group described below may be used as an additive.
  • the reducing agent examples include, for example, dithionous acid, dithionite (such as sodium dithionite), bisulfite (such as sodium bisulfite), sulfite (such as sodium sulfite and anhydrous sodium sulfite), pyrosulfite (such as sodium pyrosulfite), metabisulfite (such as sodium metabisulfite), Rongalite (CH 2 OHSO 2 Na), ascorbic acid or salts thereof (such as L-ascorbic acid and sodium L-ascorbate), erythorbic acid or salts thereof (such as sodium erythorbate), cysteine (cysteine hydrochloride is preferable), thioglycerol, ⁇ -thioglycerin, edetate (such as sodium edetate), citric acid, isopropyl citrate, dichlorisocyanurate (such as potassium dichlorisocyanurate), thioglycolate (such as sodium thi
  • L-ascorbic acid or sodium L-ascorbate is preferable.
  • One kind of reducing agent selected from the group described above may be used alone, or two or more kinds of reducing agents may be used at the same time.
  • the reducing agent need not be added depending on the conditions.
  • the concentration of the reducing agent is preferably 0.01 g/L to 150 g/L, and more preferably 0.1 g/L to 10 g/L.
  • the oxygen carrier treated by deoxygenation may be combined with one or two or more kinds of agents selected from the group consisting of a reducing agent, electrolytes, saccharides, a pH adjuster, an isotonizing agent, and a polymer substance capable of imparting a colloid osmotic pressure, to thereby form a useful pharmaceutical composition.
  • agents selected from the group consisting of a reducing agent, electrolytes, saccharides, a pH adjuster, an isotonizing agent, and a polymer substance capable of imparting a colloid osmotic pressure, to thereby form a useful pharmaceutical composition.
  • a pharmaceutical composition including the oxygen carrier and one or two or more kinds of agents selected from the group composed of electrolytes, saccharides, a pH adjuster, an isotonizing agent, and a polymer substance capable of imparting a colloid osmotic pressure refers to a pharmaceutical composition in a form allowing administration of an oxygen carrier into a living body and safe and effective development of its oxygen transport function.
  • Examples of the form of the pharmaceutical composition include a transfusion preparation, a lyophilized preparation, a kit preparation, and a prefilled syringe.
  • saccharides to be used for the pharmaceutical composition include glucose, fructose, xylitol, maltose, sorbitol, sucrose, trehalose, mannitol, glycerin, lactose, erythritol, and dextrin.
  • Examples of the pH adjuster to be used for the pharmaceutical composition include, adipic acid, ammonia water, hydrochloric acid, sodium caseinate, dried sodium carbonate, diluted hydrochloric acid, citric acid, sodium citrate, sodium dihydrogen citrate, glycine, glucono- ⁇ -lactone, gluconic acid, sodium gluconate, crystal sodium dihydrogen phosphate, succinic acid, acetic acid, ammonium acetate, sodium acetate, diisopropanolamine, tartaric acid, D-tartaric acid, L-sodium tartrate, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, triisopropanolamine, triethanolamine, and sodium salts of barbital.
  • Examples of the isotonizing adjusting agent to be used for a pharmaceutical composition include aminoethyl sulfonic acid, sodium bisulfite, potassium chloride, calcium chloride, sodium chloride, benzalkonium chloride, magnesium chloride, fructose, xylitol, citric acid, sodium citrate, glycerin, crystal sodium dihydrogen phosphate, calcium bromide, sodium bromide, sodium hydroxide, and sodium tartrate dihydrate.
  • Examples of the polymer substance capable of imparting a colloid osmotic pressure to be used for a pharmaceutical composition include dextran (low molecular weight dextran), hydroxyethyl starch (HES, average molecular weight 70,000), gelatin (modified gelatin), albumin (human live-plasma, human serum albumin, heated human plasma protein, human recombinant albumin), soda alginate, glucose, dextrose (D-glucose monohydrate), oligosaccharides (oligosaccharide), a decomposition product of polysaccharides, amino acid, and a decomposition product of protein.
  • dextran low molecular weight dextran
  • HES hydroxyethyl starch
  • albumin human live-plasma, human serum albumin, heated human plasma protein, human recombinant albumin
  • soda alginate glucose, dextrose (D-glucose monohydrate)
  • oligosaccharides oligosaccharide
  • the oxygen carrier to be used in the present invention is suspended in a phosphate buffer, a physiological saline solution, or the like.
  • the suspension is adjusted to a pH of desirably 5.0 to 8.0, and more preferably 7.0 to 7.5.
  • the suspension has a hemoglobin solution concentration of desirably 1 g/dL to 20 g/dL, and more preferably 5 g/L to 15 g/dL.
  • the suspension has a lipid concentration of desirably 2.5 g/dL to 15 g/dL, and more preferably 4.0 g/dL to 7.5 g/dL.
  • the porphyrin metal complex-including albumin or the PEG-porphyrin metal complex-including albumin has an rHSA concentration of desirably 0.5% to 25%, and more preferably 4.0% to 6.0%; and an iron content of desirably 0.3 mM to 15 mM, and more preferably 2.0 mM to 4.0 mM.
  • a pharmaceutical composition including the above-mentioned oxygen carrier containing the above-mentioned additives and the like desirably has physical properties including a colloid osmotic pressure of 1 mmHg to 50 mmHg; a crystalline osmotic pressure of 50 mOsm to 500 mOsm; and an oxygen affinity (oxygen partial pressure P 50 providing a bonding ratio between the oxygen carrier and oxygen of 50%) of 5 Torr to 50 Torr.
  • rHSA-FecycP dispersion a porphyrin metal complex-including albumin compound having an rHSA concentration of about 5% and an iron content of 3 mM.
  • the obtained liquid was subjected to degassing and carbon monoxide (hereinafter, referred to as CO) gas flow three times for carbon monoxylation of Hb (hereinafter, referred to as CO-Hb conversion) in the liquid, to thereby obtain a carbon monoxide bonded Hb solution.
  • CO carbon monoxide
  • PEG-DSGE a composite prepared by bonding polyethylene glycol (hereinafter, abbreviated as PEG) to distearyl glutaryl ester
  • PEG polyethylene glycol
  • HbV hemoglobin-encapsulated liposome
  • CO-Hb conversion rate Method of evaluating carbon monoxide ratio
  • the artificial oxygen carrier recovered with time was diluted appropriately with a 1 mM phosphate buffer (pH 7.4), and 5 mL of the resultant was sealed in an ultraviolet cell (hereinafter, abbreviated as UV cell). Then, 10 mg to 30 mg of sodium dithionite with a purity of 75% or more was added thereto, and the whole was mixed. An absorption spectrum at a wavelength of 300 nm to 700 nm was measured, within 1 minute after the mixing, by UV-vis spectroscopy.
  • UV cell ultraviolet cell
  • the absorption spectrum included a maximum absorption derived from a carbon monoxide member at a wavelength of 427 nm; a maximum absorption derived from a deoxidized artificial oxygen carrier, that is, a deoxy-member (Deoxy member) at a wavelength of 443 nm; and an isosbestic point at a wavelength of 435 nm.
  • the number of transmissions in the present procedures corresponds to the number of cycles, each in which an artificial oxygen carrier solution after completion of treatment is transferred from an artificial oxygen carrier storage vessel to vessel for recovering an oxygen carrier subjected and then returned to the hollow fiber membrane module.
  • the apparatus shown in Fig. 1 includes an artificial oxygen carrier circulation vessel 1; an oxygen-dissolved solution circulation vessel 2; a hollow fiber membrane module 3; a light source 4; an artificial oxygen carrier circulation pump 5; an oxygen-dissolved solution circulation pump 6; an oxygen-dissolved solution supply pump 7; and an oxygen supply line 8.
  • Example 1 a hollow fiber membrane module FB-50UGA (manufactured by NIPRO Corporation) was used as the hollow fiber membrane module 3 at room temperature. 200 mL of a 10 times diluted solution of the rHSA-FecycP dispersion was introduced into the artificial oxygen carrier circulation vessel 1, and the artificial oxygen carrier was circulated at a circulation rate of 200 mL/minute with the artificial oxygen carrier circulation pump 5.
  • a 50 W halogen lamp was used as the light source 4, and the hollow fiber membrane module 3 was exposed to incandescent light of about 10,000 Lx from a distance of about 5 cm directly above.
  • the artificial oxygen carrier and the hollow fiber membrane module 3 were observed visually. Further, the artificial oxygen carrier was recovered from the artificial oxygen carrier circulation vessel 1 with time, and the CO-Hb conversion rate was used for understanding the system evaluation.
  • Fig. 6 shows that the CO-Hb conversion rate ( ⁇ in Fig. 6 ) reduced to 69% in 30 minutes, 60% in 60 minutes, and 39% in 120 minutes, and carbon monoxide was removed rapidly from the artificial oxygen carrier. No denaturation of proteins and the like by concentration of the artificial oxygen carrier, no degradation in membrane performance by drying of the separation membrane, no degradation of the separation membrane by heat, or no denaturation of the artificial oxygen carrier was observed in the artificial oxygen carrier circulation vessel 1 or the hollow fiber membrane module 3.
  • rHSA-FecycP dispersion was removed carbon monoxide by using the same apparatus and sample as those in Example 1 and in the same manner as in Example 1 except that a 500 W halogen lamp was used as the light source 4 and incandescent light of about 20,000 Lx or more was supplied.
  • Fig. 6 shows that the CO-Hb conversion rate ( ⁇ in Fig. 6 ) reduced to 27% in 30 minutes. 13% in 60 minutes, and 1.5% in 120 minutes, and carbon monoxide was removed rapidly from the artificial oxygen carrier. No denaturation of proteins and the like by concentration of the artificial oxygen carrier, no degradation in membrane performance by drying of the separation membrane, no degradation of the separation membrane by heat, or no denaturation of the artificial oxygen carrier was observed in the artificial oxygen carrier circulation vessel 1 or the hollow fiber membrane module 3.
  • Comparative Example 1 differs from Example 1 in that oxygen gas is supplied instead of the oxygen-dissolved solution.
  • the apparatus shown in Fig. 2 includes: an artificial oxygen carrier circulation vessel 11; an oxygen gas supply line 12; a gas discharge line 12'; a hollow fiber membrane module 13; a light source 14; an artificial oxygen carrier circulation pump 15; and an oxygen gas supply pump 16.
  • Carbon monoxide is removed from the artificial oxygen carrier supplied from the artificial oxygen carrier circulation vessel 11 in the hollow fiber membrane module 13 by an oxygen gas supply line 12 and light from the light source 14, and the oxygen carrier is returned to the artificial oxygen carrier circulation vessel 11.
  • the oxygen gas is supplied directly into the hollow fiber membrane module 13 from the oxygen gas supply line 12 with the oxygen gas supply pump 16, and carbon monoxide is discharged while the oxygen gas is replenished.
  • Comparative Example 1 an aqueous solution of a hollow fiber membrane module FB-50UGA (manufactured by NIPRO Corporation) was used as the hollow fiber membrane module 13 in the same manner as in Example 1.
  • 200 mL of a 10 times diluted solution of the rHSA-FecycP dispersion was introduced into the artificial oxygen carrier circulation vessel 11, and the artificial oxygen carrier was circulated at a circulation rate of 200 mL/minute with the artificial oxygen carrier circulation pump 15. Meanwhile, an oxygen gas was directly blown into the hollow fiber membrane module 13 at 2,000 mL/minute with the oxygen gas supply pump 16.
  • a 50 W halogen lamp was used as the light source 14, and the hollow fiber membrane module 13 was exposed to incandescent light of about 10,000 Lx from a distance of about 5 cm directly above.
  • Fig. 6 shows that the CO-Hb conversion rate ⁇ in Fig. 6 ) reduced to 89% in 30 minutes, 74% in 60 minutes, and 55% in 120 minutes. Further, denaturation of proteins and the like by concentration of the artificial oxygen carrier, degradation in membrane performance by drying of the separation membrane, degradation of the separation membrane by heat, and denaturation of the artificial oxygen carrier were observed in the artificial oxygen carrier circulation vessel 11 or the hollow fiber membrane module 13.
  • the rHSA-FecycP dispersion was subjected to carbon monoxide removal by using the same apparatus and sample as those of Comparative Example 1 and in the same manner as in Comparative Example 1 except that a 500 W halogen lamp was used as the light source 4 and the hollow fiber membrane module 13 was exposed to incandescent light of about 20,000 or more.
  • the artificial oxygen carrier solution in the hollow fiber membrane module 13 and the artificial oxygen carrier circulation vessel 11 showed abnormal temperature increase to 65°C or higher in 20 minutes.
  • An outer covering of the hollow fiber membrane module 13 melted by heat of the 500 W halogen lamp, and the hollow fiber membrane was clogged. Denaturation of the artificial oxygen carrier solution was observed.
  • Example 2 The temperature of the artificial oxygen carrier solution in the artificial oxygen carrier circulation vessel and its change with time in Example 2 and Comparative Example 2 were studied. As a result, as shown in Fig. 8 , no increase in temperature of the artificial oxygen carrier solution was observed through use of the method of present invention as in Example 2 ( ⁇ in Fig. 8 ). However, the temperature of the artificial oxygen carrier solution far exceeded 60°C in about 20 minutes through use of a method in which an oxygen gas is supplied as in Comparative Example 2 (A in Fig. 8 ). The temperature far exceeding 60°C causes denaturation of proteins, and thus the method in which an oxygen-dissolved solution is supplied and the apparatus of the present invention are excellent in view of not causing a temperature increase.
  • the hemoglobin-encapsulated liposome dispersion was subjected to carbon monoxide removal by using the same apparatus and sample as those of Example 1 and in the same manner as in Example 1 except that the hemoglobin-encapsulated liposome dispersion was used instead of the rHSA-FecycP dispersion.
  • Fig. 7 shows that the CO-Hb conversion rate reduced to 50% in 30 minutes, 27% in 60 minutes, 8% in 120 minutes, and about 0% in 210 minutes, and carbon monoxide was removed rapidly from the artificial oxygen carrier.
  • the rHSA-FecycP dispersion was subjected to carbon monoxide removal by using the same apparatus and sample as those of Example 1 and in the same manner as in Example 1, that is, the apparatus shown in Fig. 4 except that the artificial oxygen carrier was not circulated to the artificial oxygen carrier circulation vessel 1; three hollow fiber membrane modules were connected in series; and the sample allowed to pass through the hollow fiber membrane modules was recovered continuously.
  • the apparatus of Fig. 4 includes an artificial oxygen carrier storage vessel 17; an oxygen-dissolved solution circulation vessel 18; a hollow fiber membrane module A 19; a hollow fiber membrane module B 20; a hollow fiber membrane module C 21; a light source A 22; a light source B 23; a light source C 24; an artificial oxygen carrier circulation pump 25; an oxygen carrier supply line 25'; an oxygen carrier recovery line 25"; an oxygen-dissolved solution circulation pump 26; an oxygen-dissolved solution supply line 26'; an oxygen-dissolved solution recovery line 26"; an oxygen supply line 27 and a gas discharge line 27'; and a vessel 28 for recovering an artificial oxygen carrier subjected to carbon monoxide removal.
  • the artificial oxygen carrier subjected to carbon monoxide removal can be collected continuously at 200 mL/minute.
  • the artificial oxygen carrier had a CO-Hb conversion rate of 89% after passing through the hollow fiber membrane module A, 77% after passing through the hollow fiber membrane module B, and 67% after passing through the hollow fiber membrane module C.
  • the results suggest that a pharmaceutical composition having a CO-Hb conversion rate of about 0% can be obtained continuously by increasing the number of hollow fiber membrane modules.
  • a module was prepared by applying an isocyanate-based resin in a circular pattern on the central portion of the cross section of the bundle of hollow fibers at an inlet of an inner port of the hollow fiber module so as to allow a treatment solution to run only along the outer periphery of the bundle of hollow fibers in the module, which can be easily exposed to light.
  • the bundle of hollow fibers in the port of the hollow fiber membrane module FB-210UGA has a cross-sectional diameter of 3.6 to 3.8 cm.
  • the isocyanate-based resin was applied on the cross-section of the bundle of hollow fibers so as to be applied concentrically in a circular pattern of 3.0 to 3.2 cm in diameter. Consequently, the bundle of hollow fibers in a module, which allows the treatment solution to pass through a cylindrical portion a portion in the form of a cylinder having a thickness of 2 to 4 mm.
  • an oxygen-dissolved solution circulation vessel 30 includes an oxygen-dissolved solution circulation vessel 30; an urethane-sealed hollow fiber membrane module 31; a light source A 32; an oxygen carrier circulation pump 33; an oxygen carrier supply line 33'; an oxygen carrier recovery line 33"; an oxygen-dissolved solution circulation pump 34; an oxygen-dissolved solution supply line 34'; and oxygen-dissolved solution recovery line 34"; an oxygen supply line 35; a gas discharge 35'; and a vessel for recovering an oxygen carrier subjected 36).
  • the module used was a single urethane-sealed hollow fiber membrane module 29 as shown in Fig.9 or 10 .
  • the rate of removal of carbon monoxide was decreased to, as shown in Fig. 11 , 91% by one cycle of transmission, 78% by three cycles of transmission, and 3% by ten cycles of transmission, so that removing carbon monoxide from the artificial oxygen carrier could be quickly performed. Furthermore, in the oxygen carrier circulation vessel 1 and the hollow fiber membrane module 3, no denaturation of a protein or the like due to a condensation of the artificial oxygen carrier, no decrease in membrane performance due to drying of the separation membrane, no deterioration of the separation membrane due to heat, and no alternation of the artificial oxygen carrier were observed.
  • the oxygen carrier obtained in the present invention can be used in medical fields for oxygen supply to an ischemic site or tumor tissue, for blood transfusion to a patient with massive bleeding, for an organ preservation perfusion fluid, for an extracorporeal circulation fluid, for a cell culture medium, and the like.

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Claims (3)

  1. Procédé d'élimination continue de monoxyde de carbone d'un transporteur d'oxygène lié à du monoxyde de carbone comprenant :
    l'utilisation d'une solution de transporteur d'oxygène lié à du monoxyde de carbone placée sur un côté d'une membrane de séparation (3 ; 3' ; 19 à 21 ; 31) en tant que frontière et d'une solution de dissolution de l'oxygène placée sur un autre côté de la membrane de séparation ; et
    l'exposition à la lumière de la partie de la membrane de séparation où le transporteur d'oxygène lié à du monoxyde de carbone rencontre l'oxygène de la solution de dissolution de l'oxygène,
    dans lequel la source de lumière comprend une lumière incandescente, une lampe halogène, une diode d'émission de lumière, une lampe à vapeur de sodium ou une lampe aux halogénures métalliques ; et
    la membrane de séparation comprend une membrane d'ultrafiltration ou un filtre de filtration et est de préférence une polysulfone, un triacétate de cellulose, un diacétate de cellulose, un polycarbonate, une polyéthersulfone ou un polymère polyphospholipidique.
  2. Procédé d'élimination continue de monoxyde de carbone d'un transporteur d'oxygène lié à du monoxyde de carbone selon la revendication 1, dans lequel la membrane de séparation comprend une membrane de séparation en fibres creuses (3 ; 19 à 21 ; 31).
  3. Appareil pour l'élimination continue de monoxyde de carbone d'un transporteur d'oxygène lié à du monoxyde de carbone comprenant :
    un récipient de circulation du transporteur d'oxygène (1) ;
    un récipient de circulation de la solution de dissolution de l'oxygène (2) ;
    un module membranaire en fibres creuses (3), la membrane comprenant une membrane d'ultrafiltration ou un filtre de filtration et est de préférence une polysulfone, un triacétate de cellulose, un diacétate de cellulose, un polycarbonate, une polyéthersulfone ou un polymère polyphospholipidique ;
    une source de lumière (4), la source de lumière comprenant une lumière incandescente, une lampe halogène, une diode d'émission de lumière, une lampe à vapeur de sodium ou une lampe aux halogénures métalliques ;
    une pompe de circulation du transporteur d'oxygène (5) ;
    une ligne d'alimentation du transporteur d'oxygène (5') ;
    une ligne de récupération du transporteur d'oxygène (5") ;
    une pompe de circulation de la solution de dissolution de l'oxygène (6) ;
    une ligne d'alimentation de la solution de dissolution de l'oxygène (6') ;
    une ligne de récupération de la solution de dissolution de l'oxygène (6") ;
    une pompe d'alimentation de la solution de dissolution de l'oxygène (7) ;
    une ligne d'alimentation d'oxygène (8) ;
    une vanne de contrôle du flux (9) ; et
    un agitateur et une pale sur celui-ci (10) ;
    dans lequel le récipient de circulation du transporteur d'oxygène (1) est raccordé au module membranaire en fibres creuses (3) par l'intermédiaire de la ligne d'alimentation du transporteur d'oxygène (5') et la pompe de circulation du transporteur d'oxygène (5) apporte le transporteur d'oxygène du récipient de circulation du transporteur d'oxygène (1) vers le module membranaire en fibres creuses (3) ;
    dans lequel le récipient de circulation de la solution de dissolution de l'oxygène (2) est raccordé au module membranaire en fibres creuses (3) par l'intermédiaire de la ligne d'alimentation de la solution de dissolution de l'oxygène (6') et la pompe de circulation de la solution de dissolution de l'oxygène (6) apporte la solution de dissolution de l'oxygène dans le module membranaire en fibres creuses (3) ; et
    dans lequel la source de lumière (4) est positionnée de sorte que la partie de la membrane de séparation où le transporteur d'oxygène lié à du monoxyde de carbone rencontre l'oxygène de la solution de dissolution de l'oxygène soit exposée à la lumière.
EP06007915A 2005-04-15 2006-04-13 Méthode pour ôter le monoxyde de carbone d'un transporteur d'oxygène telle l'hémoglobine et appareil associé Not-in-force EP1714691B1 (fr)

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JP2005119057 2005-04-15
JP2006038716A JP4665791B2 (ja) 2005-04-15 2006-02-16 酸素運搬体の脱一酸化炭素化方法、脱一酸化炭素化された酸素運搬体、その医薬組成物及び脱一酸化炭素化装置

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US10172950B2 (en) 2009-06-09 2019-01-08 Prolong Pharmaceuticals, LLC Hemoglobin compositions
SI2440239T1 (en) 2009-06-09 2018-01-31 Prolong Pharmaceuticals, LLC Hemoglobin compositions
US10172949B2 (en) 2009-06-09 2019-01-08 Prolong Pharmaceuticals, LLC Hemoglobin compositions
US20120157905A1 (en) * 2010-12-15 2012-06-21 Biovec Transfusion, Llc Methods for treating carbon monoxide poisoning by tangential flow filtration of blood
WO2012108855A1 (fr) * 2011-02-10 2012-08-16 Infoscitex Corporation Système à deux étapes et procédé d'oxygénation et d'extraction du dioxyde de carbone d'un fluide physiologique
US11013849B2 (en) * 2011-02-12 2021-05-25 Mark S. Smyczynski Extracorporeal photodynamic blood illumination (irradiation) cell for the treatment of carbon monoxide poisoning
US8858880B2 (en) * 2011-02-12 2014-10-14 Mark S. Smyczynski Extracorporeal photodynamic blood illumination (irradiation) for the treatment of carbon monoxide poisoning
EP3351292B1 (fr) * 2015-05-18 2019-08-21 The General Hospital Corporation Système de photothérapie pour la prévention ou le traitement d'un empoisonnement au monoxyde de carbone
US10456452B2 (en) 2015-07-02 2019-10-29 Poseida Therapeutics, Inc. Compositions and methods for improved encapsulation of functional proteins in polymeric vesicles
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EP3817796B1 (fr) 2018-07-03 2025-01-08 The General Hospital Corporation Système d'élimination extracorporelle du monoxyde de carbone par photothérapie
CA3135797A1 (fr) * 2019-04-02 2020-10-08 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Molecules d'hemoglobine modifiees et leurs utilisations
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US7601201B2 (en) 2009-10-13
ATE505257T1 (de) 2011-04-15
JP2006316042A (ja) 2006-11-24
EP1714691A1 (fr) 2006-10-25
DE602006021253D1 (de) 2011-05-26
CN1864822A (zh) 2006-11-22
CN1864822B (zh) 2011-05-04

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